Melanomas are aggressive, frequently metastatic tumors derived from either melanocytes or melanocyte related nevus cells (“Cellular and Molecular Immunology” (1991) (eds.) Abbas A. K., Lechtman, A. H., Pober, J. S.; W. B. Saunders Company, Philadelphia: pages 340-341). Melanomas make up approximately three percent of all skin cancers and the worldwide increase in melanoma is unsurpassed by any other neoplasm with the exception of lung cancer in women (“Cellular and Molecular Immunology” (1991) (eds.) Abbas, A. K., Lechtiman, A. H., Pober, J. S.; W. B. Saunders Company Philadelphia pages: 340-342; Kirkwood and Agarwala (1993) Principles and Practice of Oncology 7:1-16). Even when melanoma is apparently localized to the skin, up to 30% of the patients will develop systemic metastasis and the majority will die (Kirkwood and Agarwala (1993) Principles and Practice of Oncology 7:1-16). Classic modalities of treating melanoma include surgery, radiation and chemotherapy. In the past decade, immunotherapy and gene therapy have emerged as new and promising methods for treating melanoma.
Strong evidence that an immune response to cancer exists in humans is provided by the existence of lymphocytes within melanoma deposits. These lymphocytes, when isolated, are capable of recognizing specific tumor antigens on autologous and allogeneic melanomas in a major histocompatibility complex (MHC)-restricted fashion (Itoh et al. (1986), Cancer Res. 46: 3011-3017; Muul et al. (1987), J. Immunol. 138:989-995); Topalian et al. (1989) J. Immunol. 142: 3714-3725; Darrow et al. (1989) J. Immunol. 142: 3329-3335; Hom et al. (1991) J. Immunother. 10:153-164; Kawakami et al. (1992) J. Immunol. 148: 638-643; Hom et al. (1993) J. Immunother. 13:18-30; O'Neil et al. (1993) J. Immunol. 151: 1410-1418). Tumor infiltrating lymphocytes (TIL) from patients with metastatic melanoma recognize shared antigens including melanocyte-melanoma lineage specific tissue antigens in vitro (Kawakami et al. (1993) J. Immunother. 14: 88-93; Anichini et al. (1993) J. Exp. Med. 177: 989-998). Anti-melanoma T cells appear to be enriched in TIL probably as a consequence of clonal expansion and accumulation at the tumor site in vivo (Sensi et al. (1993) J. Exp. Med. 178:1231-1246). The fact that many melanoma patients mount cellular and humoral responses against these tumors and that melanomas express both MHC antigens and tumor associated antigens (TAA) suggests that identification and characterization of additional melanoma antigens will be important for immunotherapy of patients with melanoma.
The human chondroitin sulfate proteoglycan HMW-MAA, also know as CSPG4, is an early cell surface melanoma progression marker implicated in stimulating tumor cell proliferation, migration and invasion. Clinical studies have indicated HMW-MAA as a relevant therapeutic target because a vaccine targeting HMW-MAA in patients with melanoma immunized with HMW-MAA mimics provides significant survival advantage only to a subset of patients who developed HMW-MAA-specific antibodies, but not to those patients who did not develop them. In addition, the biologic significance of targeting HMW-MAA could be related to the role in regulating cell growth and differentiation. However, a need remains for other immunotherapeutic strategies that target this antigen.